Hemostatic parameter display

ABSTRACT

A system for displaying a plurality of hemostatic indexes is disclosed. The system includes a communication receiver configured to receive the hemostatic indexes and a graphical user interface (GUI) connected to the communication receiver and configured to simultaneously display the hemostatic indexes. The hemostatic indexes are derived from a plurality of independent measurements, such as the mechanical measurements determined using the sonorheometry systems and processes.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to and hereby incorporates byreference in its entirety U.S. provisional patent application No.61/322,049 entitled “Novel Technology for Point-of-Care Assessment ofHemostasis” and filed on Apr. 8, 2010.

FIELD OF THE INVENTION

The present invention relates to displays for physiologic parameters andmore particularly displays with graphical user interfaces (GUI) forintuitively presenting physiologic parameters for easy use andinterpretation by healthcare personnel.

BACKGROUND

The formation of a blood clot and its successive dissolution, referredto as the hemostatic process, is required to arrest blood loss from aninjured vessel. This process is the result of a delicate functionalbalance between plasma coagulation factors (including fibrinogen),platelets, and fibrinolytic proteins. Each of these elements plays animportant role in activating/deactivating the others, and theappropriate stimuli are necessary to prevent excessive blood losswithout causing inappropriate thrombosis, see Laposata M., et al., TheClinical Hemostasis Handbook, Year Book Medical Publisher 1989.

The hemostatic process is initiated by the activation and subsequentadhesion of platelets to the site of injury within the vessel wall.Activated platelets recruit other platelets and interact with fibrinogenin the blood plasma via the glycoprotein IIb/IIIa receptor to form aplatelet-plug that serves as the initial response to stop blood loss.Hemostasis then proceeds with a cascade of proteolytic reactions of theplasma coagulation proteins that ultimately form a three-dimensionalnetwork of fibrin that strengthens the platelet-plug. The fibrin chainsare cross-linked and stabilized by the plasma factor XIIIa (FXIIIa).Platelets also have a central role in regulating the process of fibrinpolymerization. The final step of hemostasis (i.e., fibrinolysis)involves the activation of the plasma protein plasmin, which dissolvesthe blood clot when its useful life is over. This cell-based model ofhemostasis closely reflects the in vivo physiological process, e.g., seeHoffman et al., “A cell-based model of hemostasis;” Thromb. Haemost.2001; 85:958-965 and Becker, “Cell-Based Models of Coagulation: AParadigm in Evolution;” J. Thromb. Thrombolysis 2005: 20:65-68.

The mechanical properties of blood clots have implications for itsfunction of stopping blood loss. Alterations in clot structure and itsunderlying mechanical properties have been implicated in thromboticdisease and other life threatening pathologies, see Weisel, J. W.,“Enigmas of Blood Clot Elasticity;” Science 2008; 320:456. Recently, itwas shown that fibrin clots of patients affected by premature coronaryartery disease have a different structure and higher stiffness comparedto the fibrin clots of healthy age-matched controls, see Collet et al,“Altered Fibrin Architecture is Associated with Hypofibrinloysis andPremature Coronary Atherothrombosis;” Arterioscler. Thromb. Vasc. Biol.2006; 26:2567-2573.

The mechanics of fibrin networks have been studied extensively at themacroscopic level see Ryan et al., “Structural Origins of Fibrin ClotRheology”; Biophys. J. 1999; 77:2813-2826 and Jen et al., “TheStructural Properties and Contractile Force of a Clot;” Cell Motil.1982; 2:445-455. The viscoelastic properties of individual fibrinstrands have also been investigated by means of AFM (see Liu et al.,“Fibrin Fibers Have Extraordinary Extensibility and Elasticity;” Science2006; 313:634) and “optical tweezers,” see Collet et al., “Theelasticity of an individual fibrin fiber in a clot;” Proc. Natl. Acad.Sci. USA 2005; 102:9133-9137.

Disruption of the hemostatic balance plays a role in the onset ofpotentially fatal conditions, including myocardial infarction, stroke,deep vein thrombosis, pulmonary embolism, and excessive bleeding, seeHoyert et al., “Deaths: preliminary data for 2003”, Natl. Vital Stat.Rep. 2005; 53:1-48 and Hambleton et al., “Coagulation: ConsultativeHemostasis”; Hematology 2002; 1:335-352. These conditions account forover 30% of all deaths in the developed world. The ability to recognizeand quantify defects of the hemostatic process may reduce mortality andimplement appropriate treatment.

Further improvements in the detection and treatment of hemostaticdefects are therefore desired.

SUMMARY

In one embodiment, the present invention includes a system fordisplaying one or more of a plurality of hemostatic indexes, the systemhaving a communication receiver and a GUI. The communication receiver isconfigured to receive the hemostatic indexes. The GUI is connected tothe communication receiver and configured to display one, orsimultaneously at least two, of the hemostatic indexes. The hemostaticindexes are derived from one or more of a plurality of independentmeasurements.

In one example, one of the indexes may be calculated from two of theindependent measurements, such as from ultrasound measurements on twosample wells containing different reagents.

The hemostatic indexes may include a coagulation factor function, afibrinogen concentration, a fibrinogen function, a platelet function anda fibrinolysis function. The coagulation factor may include at least oneof an intrinsic activiation factor or an extrinsic activation factor.The GUI may be further configured to display hematocrit, hemoglobinconcentration and red cell count simultaneously with the two hemostaticindexes.

Also, the GUI may be configured to display the functional hemostasisindexes as a numerical score or a graphical depiction or with varyingcolors.

In another embodiment, the GUI is further configured to display ahistory of the hemostatic indexes and clinical interventions overlaid onthe history. At least one portion of the history may include an array ofgraphical indicators, with each of the graphical indicators representingone of the hemostatic indexes at some time in the history. The graphicalindicators may have a relative positioning configured to communicate ahemostatic condition of the subject at that time in history.

In yet another embodiment, the GUI may be further configured to displaya treatment recommendation based on the at least two hemostatic indexes.For example, the treatment recommendation may be guiding transfusion ofplatelets, cryoprecipitate, plasma, red cells or antifibrinolytics. Or,the treatment recommendation is for guiding therapies of at least one ofan anti-platelet drug, anti-coagulant drug or pro-fibrinolysis drug.

In another embodiment, a method includes deriving a plurality ofhemostatic indexes from a plurality of independent measurements anddisplaying at least two of the hemostatic indexes.

In another embodiment, a system for measuring hemostatic characteristicsof a blood sample includes a processor and a GUI. The processor isconfigured to receive a data stream of stiffness measurements of theblood sample and to estimate a possible range of a functional hemostaticindex based on the data stream. The GUI is connected in communicationwith the processor and is configured to display the possible range ofthe functional hemostatic index.

Also, the processor may be configured to determine changes in thepossible range as new data is received from the data stream and the GUIis configured to dynamically adapt a graphical element to express thosechanges.

Advantages of embodiments of the present invention include the abilityto show two or more hemostatic indexes at the same time wherein theprior art is limited to serial tests. Another advantage is the abilityfor healthcare personnel to see the past history of various hemostaticindexes and the impact of various treatments. Additionally, healthcarepersonnel may benefit from display of trends in the hemostatic indexesand are able to more quickly apply preventive treatment in urgent caresituations.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a perspective view of a functional hemostatic indexdetermination and display system;

FIGS. 2A and 2B are diagrams of sonorheometry to determine thehemostatic indexes displayed in FIG. 1 ;

FIGS. 3A-3F show a plurality of GUI display configurations of the systemof FIG. 1 indicating different patient conditions;

FIG. 4 shows a historical display of test results with multiplehemostatic indexes at various points in history;

FIG. 5 shows a historical display with a single functional hemostaticindex as it changes during the history;

FIG. 6 is a perspective view of a functional hemostatic indexdetermination and display system testing two subjects in parallel;

FIG. 7 is a perspective view of a functional hemostatic indexdetermination and display system operating a surface activation test;

FIG. 8 is a GUI showing use of color to indicate normal and abnormaltest results;

FIG. 9 is a method for determining and displaying a plurality ofhemostatic indexes;

FIGS. 10-18 show a graphical display of a graphical element (a bar) thatdynamically shrinks as measurement confidence increases duringdetermination of a functional hemostatic index; and

FIG. 19 is a schematic of a functional hemostatic index determinationand display system as a network entity.

DETAILED DESCRIPTION

The inventors have made the following observations. Unregulatedhemostasis, manifested either as thrombotic disease or excessivebleeding, represents one of the leading causes of morbidity andmortality in the developed world. For example, millions of patients inthe United States are currently prescribed anti-platelet medications(such as aspirin or clopidogrel) or anti-coagulation drugs (such ascoumadin, heparin or direct thrombin inhibitors) to prevent theoccurrence of thrombotic conditions. However, it has been estimated that5-60% of these patients may not respond adequately to aspirin and 4-30%to clopidogrel, for example, leading to higher risks of recurringthrombotic events or excessive bleeding.

Excessive bleeding often occurs during trauma, major surgicalprocedures, and on the battlefield. In these cases, transfusion of bloodand its derived products are used in clinical practice to manageexcessive bleeding. Generally, there are four treatment optionsavailable, each corresponding to a specific hemostatic defect: (a) freshfrozen plasma (FFP) to restore the plasma coagulation proteins, (b)platelet concentrate to restore platelets, (c) cryoprecipitate torestore fibrinogen, and (d) anti-fibrinolytics to slow the activity ofthe clot-dissolving proteins. Additionally, packed red blood cells(RBCs) are administered if hematocrit or hemoglobin falls within acertain threshold level.

While transfusions of blood products have had a great impact in savinglives, blood and its derived products are scarce and have to becarefully optimized. Furthermore, transfusion therapies carry the risksof possible allergic reactions, a variety of viral and bacterialinfections, and worsened outcomes. The use of blood products isparticularly intensive in cardiac surgery involving cardio-pulmonarybypass (CPB), where over 60% of patients experience excessive intra andpost-operative bleeding.

It has been estimated that CPB surgeries account for roughly 20% of thetotal blood products used in the United States, with significantvariations in protocols and guidelines among different institutions.Intra- and post-operative bleeding in CPB is often the result of bloodbeing heavily anti-coagulated and exposed to the foreign surfaces of theextracorporeal circuitry. Loss of platelets, abnormal platelet function,hemodilution, inadequate function of the fibrinolytic system, andpatients' cooling/warming also contribute to failure of the hemostaticsystem, which has to be corrected with allogenic blood products.

Several protocols and guidelines have been developed in the past yearsto optimize transfusion therapies in order to minimize the likelihood ofnegative outcomes, save valuable resources, and generate financialsavings to the healthcare systems. Chief among those is a recent reportfrom The Society of Thoracic Surgeons Blood Conservation Guideline TaskForce in combination with The Society of CardiovascularAnesthesiologists Special Task Force on Blood Transfusions. One of thekey components of these protocols regards the use of POC diagnostictests of coagulation and platelet function to recognize abnormalities ofthe hemostatic process. In clinical practice, however, empiricalapproaches are often used, and transfusions are administered with littleor no quantitative guidance. Table I below summarizes some of theavailable treatments.

TABLE I Bleeding Patient Clotting Patient Problem with Transfuse FreshAdminister Anti- Coagulation Frozen Plasma coagulant (coumadin, Factorsheparin, direct thrombin inhibitor, etc) Problem with Transfuse N/AFibrinogen Cryoprecipitate Problem with Transfuse Platelets AdministerAnti- Platelets platelet therapy (aspirin, Plavix, etc) Problem withAdminister Anti- Administer Pro- Fibrinolysis fibrinolytic fibrinolysis(aminocaproic acid (tissue plasmino- or tranexamic acid, gen activator,etc) etc)

Current tests of hemostasis can be divided into three broad categories:endpoint biochemical assays, mechanical/viscoelastic analyzers, andplatelet-specific tests. Endpoint assays are traditionally performed onblood plasma and include such tests as the pro-thrombin time (PT/INR),activated partial thromboplastin time (aPTT), and the activated clottingtime (ACT). A variety of methodologies, ranging from optical detectionto flow impediment, are employed to determine the time required to reacha pre-defined endpoint that represents the clotting time. The output ofthese tests is generally the clotting time expressed in seconds (orminutes) or a single number selected from an arbitrary scale such as inthe case of the INR (International Normalized Ratio).

While each of these assays measures a different aspect of thecoagulation factors, even in combination they do not provide a completerepresentation of overall hemostasis. See, Gravlee et al., “Predictivevalue of blood clotting tests in cardiac surgical patients”; Ann.Thorac. Surg. 1994; 58:216-221 and Bajaj et al., “New insights into howblood clots: Implication for the use of APTT and PT as coagulationscreening tests and in monitoring anticoagulant therapy”; Semin. Thromb.Hemost. 1999; 25:407-418.

Fibrinogen level, for example, is typically measured using the standardClauss method, another end-point assay. The clotting time of plateletfree plasma is measured in the presence of thrombin and compared to acalibration curve to determine fibrinogen level. The output of this testis the concentration of fibrinogen, typically expressed in units ofmg/dl. The end point tests are further limited by the absence of activeplatelets.

In contrast, mechanical methods, such as the TEG® (Haemoscope), ROTEM®(Pentapharm), HAS (Hemodyne) and SonoClot® (Sienco), measure thecontribution of all the components of hemostasis in whole blood. Thesemethods have been widely studied and shown to offer valuable clinicaland scientific insights, see Ganter et al., “Coagulation Monitoring:Current Techniques and Clinical Use of Viscoelastic Point-of-CareCoagulation Devices”; Anesth. Analg. 2008; 106:1366-1374.

Existing mechanical methods, however, utilize complex and expensivemechanical transducers, resulting in instruments that are difficult tooperate and to interpret. The output of these systems is generally acurve that describes the overall hemostatic process along with somenumerical scores. Further, the large mechanical strains (in the range of8% to 16%) applied to the blood samples have been shown to interferewith clot formation and limit sensitivity and speed of the measurements,see Evans et al., “Rheometry and associated techniques for bloodcoagulation studies”; Med. Eng. Phys. 2008; 30:671-679 and Burghardt etal., “Nonlinear viscoelasticity and thromboelastograph: Studies onbovine plasma clots”; Biorheology 1995; 32:621-630.

The most common platelet tests are the platelet count and plateletaggregation. In a healthy patient, platelet count is between 150K and400K platelets per mm³. Platelet aggregation measures the ability ofplatelets to stick together and form small clumps. These tests aretypically performed in central laboratories using platelet rich plasma(PRP), even though whole blood assays have recently emerged. Limitationsinclude the necessity to perform the measurements with anticoagulatedblood, which does not represent actual physiology, and the longturn-around-times (>45 minutes) to obtain results from the central lab.

Embodiments of the present invention disclosed herein include systemsand methods for intuitively displaying a plurality of functionalhemostasis indexes that are directly related to the therapies availablefor both the hypo-coagulable (i.e., bleeding) and hyper-coagulable(i.e., clotting) patient. The term “hemostasis indexes” as used hereinindicates a series of measures that are related to physiologicalcomponents or parameters involved directly or indirectly in thephysiological process of hemostasis (as opposed to raw mechanicalparameters). Knowledge of the function of these physiological componentsof hemostasis can enable diagnostic decisions by healthcareprofessionals. For example, these functional hemostasis indexes mayinclude: (1) coagulation factor function, (2) fibrinogen concentrationand/or function, (3) platelet function and (4) fibrinolytic function. Asdiscussed above, the inventors have also recognized that transfusion ofpacked red cells is common in a bleeding patient. Therefore, anadditional hemostasis index represented by the hematocrit, hemoglobinconcentration or red cell count so that the system can provideinformation about additional possible transfusion products.

In one embodiment, the hemostatic indexes are determined usingsonorheometry. Coagulation factor function (when determined bysonorheometry) is the time at which significant fibrin formation occurswhich is measured as the time at which clot stiffening starts. It isdetermined by finding the point on the time-stiffness curve wherestiffness rises by an order of magnitude above baseline. Normal valuesare about 3.5 minutes with +/−10% or 0.35 minutes. Pathological valuescan fall as low as 1 minute.

Fibrinogen function (when determined by sonorheometry) is the maximumclot stiffness in the absence of platelet function. Either stiffnessunits or traditional mg/dL units may be used. It is determined as themaximum stiffness in a test well having kaolin plus ReoPro®. Normalvalues are 10⁴ in stiffness which corresponds to about 300 mg/dL. Normalvariation is about +/−5%. Pathological values range from 15 mg/dL toabove 450 mg/dL.

Platelet function (when determined by sonorheometry) is themultiplicative increase in clot stiffness that is attributed toplatelets. It is determined by dividing the maximum stiffness in a testwell with kaolin by the test well with kaolin plus ReoPro. It yields adimensionless number that normally is 10+/−1 with pathological valuesranging as low as 1.

Fibrinolytic function (when determined by sonorheometry) is the time atwhich fibrinolysis begins, and in some cases may include the effect ofan accelerant. Without an accelerant, it is determined to be the pointon the time-stiffness curve where stiffness falls by 50%. Normal isgenerally defined as 90 minutes with pathological values ranging as lowas 10 minutes. An expected range is about 60 to 120 minutes based onprior experience.

With reference now to FIG. 1 , embodiments of the present inventioninclude a system 10 for displaying a plurality of hemostatic indexes 12.The system includes a communication receiver 14 configured to receivethe hemostatic indexes 12 and a graphical user interface (GUI) 16connected to the communication receiver 14 and configured to displayone, or simultaneously at least two, of the hemostatic indexes 12. Thehemostatic indexes 12 are derived from a plurality of independentmeasurements, such as the mechanical measurements determined using thesonorheometry systems and processes described in more detail below.

The term “GUI” or “graphical user interface” as used herein includes anyhardware, software, firmware or combination thereof, or evennon-electronic interfaces, capable of generating graphical depictionssuch as liquid-crystal displays, computer monitors, cell phone or PDAscreens, televisions, tablet computers etc.

The term “independent measurement” as used herein refers to separatetests, sonorheometry or otherwise, which may be performed on a singlesample, such as a series ultrasound tests using the same instrument, oron multiple samples, such as parallel tests by multiple instruments orsensors.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, integers, steps, operations, elements,components, and/or groups thereof.

The corresponding structures, materials, acts, and equivalents of allmeans or step plus function elements in the claims below are intended toinclude any structure, material, or act for performing the function incombination with other claimed elements as specifically claimed. Thedescription of the present invention has been presented for purposes ofillustration and description, but is not intended to be exhaustive orlimited to the invention in the form disclosed. Many modifications andvariations will be apparent to those of ordinary skill in the artwithout departing from the scope and spirit of the invention. Theembodiment was chosen and described in order to best explain theprinciples of the invention and the practical application, and to enableothers of ordinary skill in the art to understand the invention forvarious embodiments with various modifications as are suited to theparticular use contemplated.

Any combination of one or more computer readable medium(s) may beutilized. The computer readable medium may be a computer readable signalmedium or a computer readable storage medium. A computer readablestorage medium may be, for example, but not limited to, an electronic,magnetic, optical, electromagnetic, infrared, or semiconductor system,apparatus, or device, or any suitable combination of the foregoing. Morespecific examples (a non-exhaustive list) of the computer readablestorage medium would include the following: an electrical connectionhaving one or more wires, a portable computer diskette, a hard disk, arandom access memory (RAM), a read-only memory (ROM), an erasableprogrammable read-only memory (EPROM or Flash memory), an optical fiber,a portable compact disc read-only memory (CD-ROM), an optical storagedevice, a magnetic storage device, or any suitable combination of theforegoing. In the context of this document, a computer readable storagemedium may be any tangible medium that can contain, or store a programfor use by or in connection with an instruction execution system,apparatus, or device.

A computer readable signal medium may include a propagated data signalwith computer readable program code embodied therein, for example, inbaseband or as part of a carrier wave. Such a propagated signal may takeany of a variety of forms, including, but not limited to,electro-magnetic, optical, or any suitable combination thereof. Acomputer readable signal medium may be any computer readable medium thatis not a computer readable storage medium and that can communicate,propagate, or transport a program for use by or in connection with aninstruction execution system, apparatus, or device.

Program code embodied on a computer readable medium may be transmittedusing any appropriate medium, including but not limited to wireless,wireline, optical fiber cable, RF, etc., or any suitable combination ofthe foregoing.

Computer program code for carrying out operations for aspects of thepresent invention may be written in any combination of one or moreprogramming languages, including an object oriented programming languagesuch as Java, Smalltalk, C++ or the like and conventional proceduralprogramming languages, such as the “C” programming language or similarprogramming languages. The program code may execute entirely on theuser's computer, partly on the user's computer, as a stand-alonesoftware package, partly on the user's computer and partly on a remotecomputer or entirely on the remote computer or server. In the latterscenario, the remote computer may be connected to the user's computerthrough any type of network, including a local area network (LAN) or awide area network (WAN), or the connection may be made to an externalcomputer (for example, through the Internet using an Internet ServiceProvider).

Aspects of the present invention are described below with reference toflowchart illustrations and/or block diagrams of methods, apparatus(systems) and computer program products according to embodiments of theinvention. It will be understood that each block of the flowchartillustrations and/or block diagrams, and combinations of blocks in theflowchart illustrations and/or block diagrams, can be implemented bycomputer program instructions. These computer program instructions maybe provided to a processor of a general purpose computer, specialpurpose computer, or other programmable data processing apparatus toproduce a machine, such that the instructions, which execute via theprocessor of the computer or other programmable data processingapparatus, create means for implementing the functions/acts specified inthe flowchart and/or block diagram block or blocks.

These computer program instructions may also be stored in a computerreadable medium that can direct a computer, other programmable dataprocessing apparatus, or other devices to function in a particularmanner, such that the instructions stored in the computer readablemedium produce an article of manufacture including instructions whichimplement the function/act specified in the flowchart and/or blockdiagram block or blocks.

The computer program instructions may also be loaded onto a computer,other programmable data processing apparatus, or other devices to causea series of operational steps to be performed on the computer, otherprogrammable apparatus or other devices to produce a computerimplemented process such that the instructions which execute on thecomputer or other programmable apparatus provide processes forimplementing the functions/acts specified in the flowchart and/or blockdiagram block or blocks.

Some embodiments of the present invention use an ultrasound-basedtechnology (“sonorheometry”) to quantify the dynamic changes inmechanical properties of whole blood during the process of coagulationand clot dissolution. This provides information about the role of thecoagulation factors, fibrinogen, platelets, and fibrinolytic proteins tooverall hemostatic function.

Sonorheometry uses the phenomenon of acoustic radiation force to makerepeated viscoelastic measurements of a whole blood sample. Acousticradiation force can be described as the transfer of momentum between anacoustic wave (or pulse) and a reflection or absorbing target. As aresult of the transferred momentum, the target experiences a smallunidirectional force in the direction of the wave (or pulse)propagation. For a perfect absorber, this can be mathematically definedas follows:

$\begin{matrix}{{❘\overset{\gamma}{F}❘} = {\frac{2\alpha\left\langle {I(t)} \right\rangle}{c} = {\frac{2\alpha{PII}}{c}{PRF}}}} & (1)\end{matrix}$

where

is acoustic radiation force (in units of m⁻¹), α is the attenuationcoefficient of the medium, c (in units of m/s) is the speed of sound inthe medium, I(t) (in units of W/m²) is the instantaneous intensity ofthe beam (e.g., ultrasound beam), PII is pulse intensity integral, andPRF is pulse repetition frequency (typically measured in hertz), whichcharacterizes the time interval between pulse or wave firings.

In order to exploit the acoustic radiation force phenomenon as a meansto discern material properties of tissue, sonorheometry can be performedas a series of pulses transmitted so that the temporal characteristic ofthe acoustic radiation force approximates a step-function. In thisstep-wise radiation force that is applied, the resultant displacementprofiles mimic responses observed in viscoelastic creep tests and can bedescribed by viscoelastic models such as the Voigt or Kelvin models.Parameters such as steady-state displacement or time constants can beextracted which characterize material properties of the tissue that theacoustic force radiation is applied to. When the target tissue is wholeblood, sonorheometry as described herein can be used to monitorcoagulation and clot dissolution properties (i.e., the hemostaticprocess).

Sonorheometry is performed using acoustic radiation force as a means togenerate small and localized displacements within a sample, e.g., awhole blood sample. Returned echoes are processed to measure the induceddisplacements and determine viscoelastic properties of the sample. In atleast one embodiment, displacements are quantified using a principalcomponent-based estimator technique, such as is described in Mauldin,Jr. et al., “Reduction of echo decorrelation via complex principalcomponent filtering,” Ultrasound Med. Biol., vol. 35, no. 8, pp.1325-1343, 2009 and in U.S. application Ser. No. 12.467,216 filed May15, 2009 and titled “Reduction of Echo Decorrelation in UltrasonicMotion Estimation.”

In performing sonorheometry according to the present invention, for eachmeasurement a series of N ultrasound pulses (where N=a positive integer)are fired toward a specified location within a blood sample at timeintervals ΔT, e.g., see FIG. 2A. Each pulse generates radiation force asenergy is absorbed and reflected during propagation. This radiationforce induces displacements within the blood sample that depend uponlocal force application and mechanical properties of the blood. Eachpulse also returns an echo as a portion of its energy is reflected fromcell/plasma interfaces within the blood. Because the tissue (blood)moves slightly from one transmission to the next, the path lengthbetween the ultrasound transducer and any given region within the target(blood) changes with pulse number. This change in path length can bereadily estimated from differences in the arrival times of echoes fromthe same region, thereby accomplishing motion tracking of the sample.The series of N acoustic pulses are sent into the blood sample at aspecified pulse repetition frequency (PRF). These pulses generateacoustic radiation force that induces a deformation field within thesample. The deformation field can be estimated from the time delays ofthe N returning echoes.

The ensemble of the time delays forms a time-displacement curve thatdescribes the viscoelastic properties of the sample being analyzed. Thisprocess is then repeated M times (where M is a positive integer), withintervening relaxation periods, to provide data about the dynamics ofclot formation and dissolution. As blood coagulates reduction indisplacement is observed. The values of the M steady-state displacementsare combined to form a relative stiffness curve that is representativeof the hemostatic process, e.g., see FIG. 2B. The stiffness parameter isreferred to as “relative” since the absolute magnitude of the radiationforce is unknown due to its dependency on blood acoustic propertieswhich change throughout coagulation. Alternatively the changes inacoustic properties (i.e., changes in acoustic attenuation a and speedof sound c) can be measured using a known reflector so that acousticradiation force can be calculated and absolute stiffness values can becalculated.

In FIG. 2B, the relative stiffness curve shows characteristic featureslabeled Time to Clot (TC1), Time to Final Clot (TC2), Angle (Θ), FinalStiffness (S), Beginning of Fibrinolysis (TL1) and End of Fibrinolysis(TL2). The hemostasis parameters indicated in FIG. 2B are calculated byfirst fitting the sonorheometry relative stiffness data to a modifiedsigmoidal function such as, for example, the following model (althoughother models may be alternatively used to accomplish these calculations,such as a combination of linear trends or a combination of skewed errorfunctions):

$\begin{matrix}{{f(t)} = {{\alpha\frac{t^{B}}{1 + e -^{(\frac{t - \gamma}{\delta})}\sigma}} + \varepsilon}} & (2)\end{matrix}$

where t is experimental time (in seconds) and α, β, γ, δ and ε areparameters determined to best fit the model curve to the data.

The parameter TC1 corresponds to the rapid increase in relativestiffness, indicating the beginning of fibrin polymerization. Similarly,the parameter TC2 represents the ending of fibrin polymerization. TC1and TC2 are calculated based on a threshold value of the derivativecurve of the relative stiffness (20% of the minimum value). The angle Θis the slope of the relative stiffness during fibrin polymerization,which extends generally between TC1 and TC2. The angle, defined as theslope of the line between TC1 and TC2, is indicative of the rate offibrin polymerization. The final stiffness S (maximum stiffness)corresponding to the maximum stiffness of the clot. The maximumstiffness S depends upon platelet function and the stiffness of thefibrin network. The times TL1 and TL2 can be defined to represent theinitial and final phases of the fibrinolytic process and the consequentdissolution of the fibrin network (time to lysis). TL1, indicating the“lysis initiation time”, and TL2, indicating the “end of lysis time”,can be calculated by defining a new sigmoidal curve similar to thatdefined by equation (2), calculating the curve derivative, andestimating the times corresponding, for example, to twenty percent ofthe minimum of the derivative. A summary of the parameters generated ispresented in Table II below:

TABLE II TC₁, TC₂ Measure initial and final Function of fibrinogen andfibrin formation other coagulation factors S Fibrin and plateletactivity Function of fibrin network and platelet aggregation Θ Rate offibrin Function of fibrinogen and polymerization other coagulationfactors TL₁, TL₂ Clot dissolving process Function of fibrinolyticproteins of the plasma

In order to isolate the four main components of hemostasis, foursonorheometry measurements can be performed in parallel using acombination of agonists and antagonists reagents. In a possibleembodiment, test well 1 may have kaolin powder to activate coagulationthrough the intrinsic pathway. Test well 2 may have a combination ofkaolin and abciximab (ReoPro) to inhibit platelet aggregation. Test well3 may have abciximab and thrombin to activate coagulation through thecommon pathway. Test well 4 may have tissue factor to activatecoagulation through the extrinsic pathway. In one embodiment, themeasurements in each well can be combined to form hemostatic indexes asshown in the Table III below:

TABLE III Coagulation factors function Time to clot TC₁ in well #1(Intrinsic Pathway) Coagulation factors function Time to clot TC₁ inwell #4 (Extrinsic Pathway) Platelets function Stiffness S differentialbetween well #1 and well #2 Fibrinogen function Stiffness S in well #3Fibrinolysis function Time to lysis TL₁ in well #4

The measurements of hematocrit (HCT), hemoglobin concentration (HGB) andred cell count (RBC) can be performed using ultrasound signals bymethods such as those disclosed in U.S. Prov. Pat. App. No. 61/443,084filed on Feb. 15, 2011 and entitled “CHARACTERIZATION OF BLOODPARAMETERS INCLUDING HEMATOCRIT AND HEMOSTASIS,” and hereby incorporatedin its entirety by reference.

In other embodiments, the hemostatic indexes may be obtained for displayfrom one or more diagnostic devices that provide information regardingthe process of coagulation and fibrinolysis (i.e., the hemostaticprocess). Such devices include, for example, methods based on directmeasurements of blood viscoelasticity such as the TEG® (Haemoscope),ROTEM® (Pentapharm), HAS (Hemodyne) and SonoClot® (Sienco).

Referring again to FIG. 1 , the system 10 of the present inventionincludes a base 18, a housing 20 containing various electroniccomponents and software such as the communication receiver 14, a pair ofconsumable receptacles 22 holding consumables 24, and the GUI 16.

The base 18 is constructed of a molded plastic and includes a foot 26 orflange for resting upon a flat surface, such as a patient's bedside, anda post 28 extending upwards therefrom to support the housing 20.Advantageously, the space between the bottom edge of the housing 20 andthe top of the foot 26 provides room for resting a storage container ofthe consumables 24. The base 18 may also function as a passage forwiring, power, communication or otherwise, connecting to the electronicswithin the housing 20 or the GUI 16.

The housing 20 includes a plurality of walls in a rectangulararrangement that is supported by the post 28 of the base 18 in aninclined, near vertical orientation for easy viewing by and interactionwith healthcare personnel. Contained within the housing 20 may bevarious combinations of hardware, software, firmware and otherelectronics to support the application of sonorheometry to theconsumables 24, operation of the GUI 16 (such as through a video card ordriver) and other functions.

For example, selected components of FIG. 19 (described in more detailbelow) may be included within the housing 20 to enable the functions andprocesses described herein. Alternatively, the housing 20 may onlycontain very basic components for displaying the results ofsonorheometry. For example, the communication receiver 14 may be a videocard or video driver, a wireless receiver or basic hardware and softwarefor communicating with cloud-based or other distributed processing powerto receive the hemostatic indexes 12 and other information.

The housing 20 includes a front screen 30 comprised of a transparentplastic that includes a central raised portion and a pair of lateralportions. The portions define planar surfaces. The lateral portions areon either side of the central raised portion and are recessed or spacedbehind the central raised portion. The recessed position of the lateralportions provides clearance for the consumables 24 and defines theconsumable receptacles 22, as shown in FIG. 1 . The pair of consumablereceptacles 22 are defined by the lateral portions of the front screen30 and generally are slots or openings sized to receive the consumables24 to provide testing access (such as by sonorheometry) to one or moreblood samples.

The central portion houses a display or other screen or device uponwhich the GUI is presented.

For example, the consumables 24 may include a cartridge or card 32connected to a syringe 34. The card 32 includes an array of multiplechambers or wells 36 in a side-by-side or serial relationship that areaccessible by the syringe 34 via an inlet and channels defined in thecard 32 that distribute portions of the blood into the wells. Withineach of the wells 36 is a blood sample dispensed by the syringe 34 andusually one or more reagents, such as is described in U.S. Prov. Pat.App. No. 61/443,088 filed on Feb. 15, 2011 and entitled, “Devices,Systems and Methods for Evaluation of Hemostasis,” hereby incorporatedin its entirety herein by reference. Different numbers of wells arepossible, such as 2, 3 or 4 wells.

The term “blood sample” as used herein should be construed broadly toinclude such things as plasma or whole blood or some component of wholeblood. For example, a blood sample may include blood, platelet poorplasma (PPP) or platelet rich plasma (PRP). If PPP or PRP are used forsonorheometry, however, ultrasound scattering material may be used inorder to provide adequate ultrasound scattering to perform themeasurements. For example, polystyrene beads can be used as they haveneutral buoyancy in plasma.

Generally, when used herein the term “array” refers to spaced objectsextending in a particular direction. The array configuration, however,could be any cluster or arrangement of the wells 36, not necessarily alinear one, wherein spacing along one axis is generally regular. Thus,the other axes could be somewhat offset from each other wherein theobjects in the array extend in a common direction on one axis but arestaggered above and below that axis. In the embodiment of FIG. 1 , thewells 36 are in a serial array where they are not only regularly spaced,but in a straight line.

Disposed on one side of each of the wells 36 is a lens for coupling withand focusing sound or sonic energy emitted by corresponding sensors withoperation supported by the electronics of the housing 20. This sonicenergy is used to detect the mechanical parameters of the blood samplesin the wells 36 which in turn are used to determine the hemostaticindexes using the principals described hereinabove.

In some embodiments of the present invention the GUI 16, includes aplurality of display portions 38 that are adjacent to and in a similarorientation to the sample wells 36. For example, the hemostatic indexes12 may be depicted by an array of a similar number and orientation ofgraphical elements.

Each of the display portions 38 is configured to readily depict for easyinterpretation, such as through numbers, colors or images, one of thehemostatic indexes 12. For example, the display portions 38 may includehorizontal colored bars and percentage numbers that show parameters thatinclude a coagulation factor function, a fibrinogen function (orconcentration), a platelet function and/or a fibrinolysis function.

The colors of the colored bars may be used as a theme throughout thedisplay and accompanying instructions and/or written documentation toassociate information on a single one of the hemostatic indexes 12. Forexample, all items and documentation regarding the coagulation factorcould be shown in red, the fibrinogen function in yellow, plateletfunction in purple and fibrinolytic function in light blue. In thismanner, a healthcare person has a way to quickly associate variousdisplay items and documentation with the single function under stressfuland fast-moving conditions.

The GUI 16 may also include a normal line 40 that when reached by thedisplay portion visual indicator evidences a normal condition of thesample being tested.

Advantageously, the GUI is configured, through its display of therelative positioning of multiple (such as four) hemostatic indexes 12,to characterize hemostatic function and guide medical treatment. FIG.3A, for example, shows a GUI from a hypothetical normal patient with nohemostatic defect. All of the hemostaic indexes 12 are at the same 100%(middle) level.

FIG. 3B shows a GUI from a hypothetical patient with reduced function ofthe coagulation factors (below 100%). This could be the consequence ofanti-coagulation drugs, for example. Otherwise, in the case of ableeding patient, fresh-frozen plasma can be administered to restorefunction of the coagulation factors.

FIG. 3C shows a GUI of a hypothetical patient with reduced plateletfunction, such as in the case of the patient receiving clopidogrel(Plavix®) or aspirin therapy. Otherwise, in the case of a bleedingpatient, this readout indicates that platelet concentrates should beadministered to restore platelet number and function to the patient.

FIG. 3D shows a GUI of a hypothetical patient with increasedfibrinolytic function. In this case, a bleeding patient should beadministered an anti-fibrinolytic drug such as aminocaproic acid ortranexamic acid.

FIG. 3E shows a GUI of a hypothetical patient with reduced function ofboth coagulation factors and platelets. The reduction in plateletfunction is more severe than that showed previously in FIG. 3C. In thecase of a bleeding patient, the GUI of FIG. 3E indicates the need totransfuse fresh frozen plasma along with platelet concentrates.

FIG. 3F shows a GUI of a hypothetical patient with an increased functionof the coagulation factors. The GUI is thus indicating a need foradministration of anti-coagulant drugs such as coumadin, heparin, ordirect thrombin inhibitors, for example, to restore normal function.

In another potential embodiment, the display of coagulation factors isdivided into intrinsic and extrinsic coagulation factors to indicatedefects that are specific to each activation pathway. The function ofthe intrinsic and extrinsic coagulation factors would be displayed alongwith the function of platelets, fibrinogen and fibrinolysis.

FIGS. 6 and 7 show other embodiments in which numerical scores arepresented to quantify the function of the hemostatic components.Numerical scores can be presented as an arbitrary percentage or on anarbitrary numerical scale. In FIGS. 6 and 7 , for example, the GUIdisplays 100% for normal physiological function. Also shown (except forfibrinogen) is display of an arbitrary scale going from 0 to 10 with 5.0representing normal physiological function. Also, a light gray baracross the display represents the line 40 of normal physiologicalhemostasis.

Units of measure could also be used to quantify the absoluteconcentration or number of some of the output parameters. In FIGS. 6 and7 , functional fibrinogen concentration is quantified in units of mg/dl,for example.

The GUI 16 may also be configured to display the type of testadministered to the blood samples. In FIG. 7 , a Surface Activation Testis performed with the use of kaolin or celite, for example, to activatecoagulation through the intrinsic (i.e., contact) activation pathway.Different types of tests and activations can be performed by selectingthe appropriate reagent set which is detected by the system 10 from thepre-loaded consumables 24, such as through an RFID tag, and thencommunicated through the GUI 16.

FIG. 6 shows an embodiment simultaneously using two consumablereceptacles 22 for parallel testing of blood samples. As in priorembodiments, the solid normal line 40 across the GUI 16 indicates normalphysiological conditions.

The GUI 16 may also be configured to dynamically change colors dependingupon the status of the various hemostatic indexes 12. As shown in FIG. 8for example, the graphical elements and numbers are color-coded withgreen representing normal, red representing increased function, andyellow representing reduced function.

In yet another embodiment, the GUI 16 may be configured to displayadditional hemostatic parameters such as: hematocrit (HCT), hemoglobinconcentration (HGB) and/or red cell count (RBC). Display of the HCT, HGBor RBC values may inform the healthcare personnel to transfuse packedred blood cell units into a bleeding patient. Therefore, combining HCT,HGB, or RBC with the hemostatic indexes 12 can provide information aboutevery possible transfusion product.

In other embodiments, the GUI 16 may be configured to display temporalprogression of the hemostatic parameters. Such a display illustrates theprogression of each hemostatic parameter as a function of proceduretime, administered treatment (transfusions) and other landmark events.

FIG. 4 , for example, shows three tests performed at three times (9:32AM; 10:17 AM and 10:51 AM) during an hypothetical procedure in whichboth consumable receptacles (A and B) are used. Time relative to thebeginning of the procedure is shown in the bottom scale, whereasabsolute time is on the top scale. For each test performed there is anarray of four color-coded symbols representing the four hemostaticindexes 12.

FIG. 5 shows an embodiment wherein a single hemostatic parameter can beselected for temporal display by the GUI 16. In this case fibrinogen inmg/dL is shown as a function of procedure time.

In another embodiment, as shown in FIG. 9 , the present inventionincludes a method for deriving and displaying hemostatic indexes.Mechanical properties of blood samples are measured 100 to generateindependent measurements. The hemostatic indexes are derived 110 fromthe independent measurements. For example, one or more of a coagulationfactor function, a fibrinogen concentration, a fibrinogen function, aplatelet function and a fibrinolysis function may be derived in step110. Also derived 110 from the independent measurements may be ahematocrit, hemoglobin concentration and/or red cell count.

Deriving 110 may also include deriving each of the hemostatic indexesfrom a plurality of the independent measurements. Also, deriving 110 mayinclude deriving each of the hemostatic indexes from a corresponding oneof the independent measurements.

The method may also include displaying 120 the hemostatic indexes, suchas by using the GUI 16. For example, displaying 120 may includedisplaying a numerical score and/or a graphical element for thehemostatic indexes. Also, displaying 120 may include displaying achanging color to indicate dynamic changes in the hemostatic indexes ora same color to associate the hemostatic indexes with other information.

The method may also include estimating or calculating 125 and displaying130 hematocrit, hemoglobin concentration and/or red cell countsimultaneously with the at least two hemostatic indexes.

The method may also include displaying 140 a history of the hemostaticindexes and overlaying 150 one or more clinical interventions on thehistory. For example, displaying 140 the history may include displayingan array of graphical indicators each representing one of the hemostaticindexes at some time in the history. The graphical indicators may bepositioned relative to each other to communicate a hemostatic conditionof a subject at that point in time.

The method may also include displaying 160 a treatment recommendationbased on the at least two hemostatic indexes. For example, the GUI 16could display information guiding transfusion of at least one ofplatelets, cryoprecipitate, plasma, red cells or antifibrinolytics, orguiding therapies using an anti-platelet drug, anti-coagulant drug orpro-fibrinolysis drug.

In another embodiment, the system 10 is configured to determine a rangeof possible values given the current results of the measurements of theblood sample. In this manner, the healthcare personnel may receive earlyindication of trend without having to wait the fully elapsed time. Forexample, as shown by the progression from FIGS. 10-18 , determination ofcoagulation factor function becomes progressively more confident asindicated by the vertical bar displayed by the GUI 16 on the right andthe associated numerical information.

Each of the figures is a 60 second interval, starting with time zero inFIG. 10 wherein a zero to infinite range of the possible 100% normalizedindex is shown. As each time interval passes, the range and accompanyingheight of the bar shrinks to express increasing certainty around theprojected result. At 1 minute the range is 0-300; at 2 minutes 0-200; at3 minutes 0-100 (since normal is 3.5 minutes +/−10% CF will definitelynot be high with no change in the stiffness); at 4 minutes 0-75 (now thepatient must be in low territory because they're outside the normalrange at the 3.85 minute high end); at 5 minutes the range drops to0-60; at 6 minutes 0-50; at 7 minutes 0-43 and with the final result at8 minutes of 38.

Notably, the GUI 16 is configured to continuously shrink the height ofthe bar (or other visual characteristic) to show increasing confidencewith the final minimum thickness and a white line indicating the finalresult.

Referring now to FIG. 19 , a schematic diagram of a central server 500,or similar network entity, configured to implement a VPD system,according to one embodiment of the invention, is provided. As usedherein, the designation “central” merely serves to describe the commonfunctionality the server provides for multiple clients or othercomputing devices and does not require or infer any centralizedpositioning of the server relative to other computing devices.

As may be understood from FIG. 19 , in this embodiment, the centralserver 500 may include a processor 510 that communicates with otherelements within the central server 500 via a system interface or bus545. Also included in the central server 500 may be a displaydevice/input device 520 for receiving and displaying data, such as viathe GUI 16 described above. This display device/input device 520 may be,for example, a keyboard or pointing device that is used in combinationwith a monitor. The central server 500 may further include memory 505,which may include both read only memory (ROM) 535 and random accessmemory (RAM) 530. The server's ROM 535 may be used to store a basicinput/output system 540 (BIOS), containing the basic routines that helpto transfer information across the one or more networks.

In addition, the central server 500 may include at least one storagedevice 515, such as a hard disk drive, a floppy disk drive, a CD Romdrive, or optical disk drive, for storing information on variouscomputer-readable media, such as a hard disk, a removable magnetic disk,or a CD-ROM disk. As will be appreciated by one of ordinary skill in theart, each of these storage devices 515 may be connected to the systembus 545 by an appropriate interface. The storage devices 515 and theirassociated computer-readable media may provide nonvolatile storage for acentral server. It is important to note that the computer-readable mediadescribed above could be replaced by any other type of computer-readablemedia known in the art. Such media include, for example, magneticcassettes, flash memory cards and digital video disks.

A number of program modules may be stored by the various storage devicesand within RAM 530. Such program modules may include an operating system550 and a plurality of one or more (N) modules 560. The modules 560 maycontrol certain aspects of the operation of the central server 500, withthe assistance of the processor 510 and the operating system 550. Forexample, the modules may include a measurement module 562 for measuringmechanical properties of a blood sample, a hemostatic indexdetermination module 564 and a display module 566.

The flowchart and block diagrams, such as in FIGS. 9 and 19 , illustratethe architecture, functionality, and operation of possibleimplementations of systems, methods and computer program productsaccording to various embodiments of the present invention. In thisregard, each block in the flowchart or block diagrams may represent amodule, segment, or portion of code, which comprises one or moreexecutable instructions for implementing the specified logicalfunction(s). It should also be noted that, in some alternativeimplementations, the functions noted in the block may occur out of theorder noted in the figures. For example, two blocks shown in successionmay, in fact, be executed substantially concurrently, or the blocks maysometimes be executed in the reverse order, depending upon thefunctionality involved. It will also be noted that each block of theblock diagrams and/or flowchart illustration, and combinations of blocksin the block diagrams and/or flowchart illustration, can be implementedby special purpose hardware-based systems that perform the specifiedfunctions or acts, or combinations of special purpose hardware andcomputer instructions.

The corresponding structures, materials, acts, and equivalents of allmeans or step plus function elements in the claims below are intended toinclude any structure, material, or act for performing the function incombination with other claimed elements as specifically claimed. Thedescription of the present invention has been presented for purposes ofillustration and description, but is not intended to be exhaustive orlimited to the invention in the form disclosed. Many modifications andvariations will be apparent to those of ordinary skill in the artwithout departing from the scope and spirit of the invention. Theembodiment was chosen and described in order to best explain theprinciples of the invention and the practical application, and to enableothers of ordinary skill in the art to understand the invention forvarious embodiments with various modifications as are suited to theparticular use contemplated.

1. A system for displaying a hemostatic index, the system comprising: acommunication receiver configured to receive the hemostatic index; and agraphical user interface (GUI) connected to the communication receiverand configured to display a hemostatic index; wherein the hemostaticindex is derived from a plurality of independent measurements.
 2. Asystem of claim 1, wherein the communication receiver is configured toreceive at least two hemostatic indexes and the GUI is configured todisplay the at least two hemostatic indexes simultaneously.
 3. A systemof claim 2, wherein at least one of the hemostatic indexes is derivedfrom a combination of at least two of the independent measurements.
 4. Asystem of claim 2, wherein each of the hemostatic indexes is derivedfrom a corresponding one of the independent measurements.
 5. A system ofclaim 2, wherein the independent measurement is a measurement ofmechanical properties.
 6. A system of claim 5, wherein the functionalhemostasis indexes include at least one of a group consisting of acoagulation factor function, a fibrinogen concentration, a fibrinogenfunction, a platelet function and a fibrinolysis function.
 7. A systemof claim 6, wherein the functional hemostasis indexes include anumerical score.
 8. A system of claim 6, wherein the functionalhemostasis indexes include a graphical depiction.
 9. A system of claim6, wherein the coagulation factor function includes at least one of anintrinsic activation factor or an extrinsic activation factor.
 10. Asystem of claim 6, wherein the GUI is further configured to display atleast one of a group consisting of a hematocrit, hemoglobinconcentration and red cell count.
 11. A system of claim 10, wherein theGUI is further configured to display the at least one of the groupconsisting of the hematocrit, hemoglobin concentration and red cellcount simultaneously with the at least two hemostatic indexes.
 12. Asystem of claim 2, further comprising a consumable receptacle configuredto receive a consumable holding at least two blood samples, wherein theblood samples are used to generate the independent measurements.
 13. Asystem of claim 12, wherein each of the blood samples is used togenerate a corresponding one of the independent measurements.
 14. Asystem of claim 10, wherein the consumable receptacle is configured toposition the at least two blood samples in a spatial arrangementcorresponding to the display of the at least two hemostatic indexes. 15.A system of claim 12, wherein the corresponding spatial arrangementincludes a side-by-side serial arrangement of both the blood samples andthe hemostatic indexes.
 16. A system of claim 2, wherein the GUI furthercomprises a visual element associating the display of each of the atleast two hemostatic indexes with the at least two blood samples.
 17. Asystem of claim 14, wherein the visual element includes at least one oflines or colors.
 18. A system of claim 2, wherein the GUI is furtherconfigured to display a history of the hemostatic indexes.
 19. A systemof claim 18, wherein the GUI is further configured to display a clinicalintervention overlaid on the history.
 20. A system of claim 18, whereinat least one portion of the history includes an array of graphicalindicators, each of the graphical indicators representing one of thehemostatic indexes at some time in the history. 21.-48. (canceled)